Assessment of murine lung mechanics outcome measures: alignment with those made in asthmatics

Abstract

Although asthma is characterized as an inflammatory disease, recent reports highlight the importance of pulmonary physiology outcome measures to the clinical assessment of asthma control and risk of asthma exacerbation. Murine models of allergic inflammatory airway disease have been widely used to gain mechanistic insight into the pathogenesis of asthma; however, several aspects of murine models could benefit from improvement. This review focuses on aligning lung mechanics measures made in mice with those made in humans, with an eye toward improving the translational utility of these measures. A brief description of techniques available to measure murine lung mechanics is provided along with a methodological consideration of their utilization. How murine lung mechanics outcome measures relate to pulmonary physiology measures conducted in humans is discussed and we recommend that, like human studies, outcome measures be standardized for murine models of asthma.

Keywords: airway hyperresponsiveness; asthma; lung mechanics; murine; translational research.

Figure 1

Examples of routine methods of Respiratory mechanics Measurements for AHR: each panel illustrates animal instrumentation, airway measurement (s) and presence of mechanical or spontaneous ventilation. (A) Airway Pressure Time Index: APTI measures the tracheal pressure response to MCh in a mouse to calculate an aggregate change in respiratory system impedance (Levitt and Mitzner, 1988). (B) Flow Plethysmography: Flow and tracheal pressure (P_tr) signals derived from a flow-plethysmograph and tracheal cannula are used to calculate Rrs or RL depending on whether transrespiratory or transpulmonary pressure is measured (Amdur and Mead, ; Waldron and Fisher, 1988). (C) End-Inflation Occlusion: This technique relies on a purpose built ventilator to deliver and hold known inflation volumes and measure the resultant pressure peak and plateau pressures to calculate Rrs and Crs (Ewart et al., ; Volgyesi et al., 2000). Ventilators may be lab constructed or use a commercial product (Volgeysi ventilator). (D) Forced Oscillation Technique: The FOT method relies on a purpose built ventilator requiring sophisticated software for the control of volume perturbations and analysis of generated pressure, volume and flow signals. In brief, ventilator housed pistons generate a complex frequency perturbation in the volume signal administered to mice. The lung response is measured as pressure from which lung impedance and other variables are calculated. Current use applications in the literature appear to be restricted to a commercially built ventilator (Scireq®flexivent).

Figure 2

Non-invasive method to measure respiratory mechanics. Mid-Expiratory Flow: Flow is measured at 50% of the expired volume (EF₅₀) from animals placed in a head-out plethysmograph. A pneumotach placed in the chamber, face mask (in humans) or tracheal cannula can be used to measure flow and volume (Vijayaraghavan et al., ; Glaab et al., 2001). This method provides an indirect assessment of resistance since the reduction in flow reflects any source of airway narrowing from pulmonary airways to changes in laryngeal adduction or even post inspiratory activation of the diaphragm.

Figure 3

Changes in baseline resistance are measureable in mice. Baseline resistance was measured using the forced oscillation technique in anesthetized, paralyzed, tracheotomized mice 24 h after the last OVA challenge (Lin et al., 2012). Duplicate measures of baseline resistance were made in all mice. Animal experiments used to acquire these data were approved by the Duke IACUC. (A) and (B) BALB/C mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2.5 mg alum on days 0 and 14 and challenged by aerosol exposure with 1% OVA for 1 h on days 21, 22, and 23 (Walker et al., 2003). The effect of 60 ug/kg i.v. albuterol on baseline resistance was assessed 1 min after it was administered. (B) C57BL/6J mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2 mg alum on days 1 and 6 and challenged by intranasal insufflation 25 μL OVA (0.2% w/v in saline) containing 2.5 nM of short scrambled peptide. ^*p < 0.05 from naïve (A) or pre-albuterol (B) as assessed by student's t-test.